KR910007238B1 - Amino-substituted briged azabicyclic quinolone carboxylic acids and esters - Google Patents

Abstract

Compounds of the formula <CHEM> wherein R<1> is hydrogen, C1-C6 alkyl, or a pharmaceutically acceptable cation; Y is cyclopropyl, ethyl or p-fluorophenyl, and X is hydrogen or fluoro, or X and Y taken together form a group <CHEM> wherein R<3> is hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof, have antibacterial properties.

Description

Amino-Substituted Crosslinked Azabicyclic Quinolone Carboxylic Acids and Esters

The present invention relates to substituted crosslinked-azabicycloalkyl quinolone carboxylic acids and esters, antimicrobial compositions containing them, their use and intermediate compounds for their preparation.

European Patent Application No. 86307045.5 (Publication No. 0215650) and US Pat. No. 4,571,396 mention amino-substituted crosslinked azabicycloalkyl quinolone carboxylic acids and esters, and antimicrobial compositions containing the compounds. European Patent Application No. 83305148.5 (Publication No.0106489) and International Application No. PCT / US 87/01583 mention crosslinking-diazabicycloalkyl quinolone carboxylic acids and esters, and antimicrobial compositions containing these compounds.

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.

또는

그룹을 형성하며: R²는

(여기에서, R³는 수소 또는 C₁-C₄알킬이다)이다.Wherein R ¹ is hydrogen, C ₁ -C ₆ alkyl or a pharmaceutically acceptable cation, Y is cyclopropyl, ethyl or p-fluorophenyl, X is hydrogen or fluorine, or X and Y together

or

Form a group: R ² is

Wherein R ³ is hydrogen or C ₁ -C ₄ alkyl.

The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an antimicrobial effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides a method for treating an animal, including a human, comprising an antimicrobially effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a bacterial disease.

The present invention also relates to a process for the preparation of compounds of formula (I) and to intermediate compounds for the preparation of compounds of formula (I). Such intermediate compounds include compounds of the general formulas (2) to (9) described below, specifically optical isomers and racemic mixtures of the compounds of the general formulas (2) to (4) and (7) to (9), and general formula Optical isomers of the compounds (5) and (6) are included.

The compounds of the present invention may have a chiral center in light of the crosslinking structure that produces monoisomers. These stereoisomers may be designated R and S according to standard nomenclature. Compounds of the present invention include racemic mixtures and optical isomers.

Preferred compounds of the invention are compounds of formula (I), wherein R ¹ is hydrogen or a pharmaceutically acceptable cation such as sodium or potassium.

Especially preferred compounds are compounds of formula (I), wherein R ¹ is hydrogen or a pharmaceutically acceptable cation.

Specific preferred compounds are as follows.

The pharmaceutical composition of the present invention preferably contains the above-mentioned preferred compounds and certain preferred compounds.

Compounds of formula (I) can be prepared by reacting compounds of formula (II) with compounds of formula R ² H, wherein R ² is as defined above.

Wherein R ¹ , X and Y are as defined above with respect to general formula (I) above and Z is halogen (eg fluorine, chlorine or bromine).

The reaction can be carried out in the presence or absence of a solvent, preferably at elevated temperatures, for a time sufficient to substantially complete the reaction. The reaction can be carried out with inorganic or organic bases, for example alkali or alkaline earth metal carbonates or bicarbonates or tertiary amines (eg triethylamine), pyridine, picoline or 1,8-diazabicyclo [5.4.0]. Preference is given to performing in the presence of an acid acceptor such as Undec-7-ene (DBU).

The reaction solvent is a solvent which is non-reactive under the reaction conditions, such as acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide (DMSO), dimethylformamide, pyridine, water or mixtures thereof.

The reaction temperature is generally in the range of about 20 ° C to about 150 ° C.

Starting materials of general formula (II) are known in the art and are described, for example, in European Patent Application No. 86307045.4 (Publication No. 0215650).

(여기에서, R³는 상기 정의한 바와 같다)를 갖는다. 상기 화합물은 하기에 나타낸 바와같이 제조할 수 있다.Starting materials of the general formula R ² H is

Wherein R ³ is as defined above. The compound can be prepared as shown below.

Compounds of formulas (2) and (3) were synthesized using N-benzyl derivatives using (S)-(-)-1-phenethylamine instead of benzylamine (JW Hoffman et al. Chem., 32, 700 (1967)). These compounds are diastereoisomers and can be separated by silica gel chromatography and / or fractional crystallization. The absolute stereochemistry of (2) and (3) was determined based on the X-ray crystallography test of (3). After the reaction of (6) and benzylamine, two diastereomers (7) and (8) are produced by reduction, which are separated by silica gel chromatography. The relative stereochemistry (exo and endo) of (7) and (8) was determined by investigation of the ¹ H-NMR ultrafine splitting constant of proximal to the benzylamino group.

Pharmaceutically acceptable acid addition salts of compounds of formula (I) are prepared in a conventional manner by treating a solution of the free base of formula (I) or suspension with at least one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are used to isolate the salts. Examples of suitable acids include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid and There is sulfonic acid.

Pharmaceutically acceptable cation salts of compounds of formula (I) may be prepared by conventional methods from the corresponding acids, for example by reaction with about 1 equimolar amount of base. Examples of suitable cationic salts are salts of alkali metals such as sodium or potassium, salts of alkaline earth metals such as magnesium or calcium and salts of ammonium or organic amines such as diethanolamine or N-methylglucamine .

Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof are useful for the treatment of widespread bacterial infections, in particular Gram-positive bacterial infections.

The compounds of the present invention may be administered alone, but are usually administered in admixture with a pharmaceutical carrier selected with respect to the desired route of administration and standard pharmaceutical practice. For example, a compound of the invention may be a tablet containing an excipient (e.g. starch or lactose) or an excitre or suspension containing a capsule or flavoring agent or colorant mixed with a capsule or excipient alone with the compound of the invention. It can be administered orally. For animals, it is advantageous to include the compound of the invention in an animal feed or beverage at a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm. The compounds of the invention can be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, it is most preferred to use the compounds of the invention in the form of sterile aqueous solutions containing sufficient salt or glucose to form other solutes, for example isotonic solutions. In animals, the compound is administered intramuscularly or subcutaneously by dividing the dose from about 0.1 to about 50 mg / kg / day, advantageously from about 0.2 to about 10 mg / kg / day in a single daily dose or in divided doses up to three times. May be administered.

The present invention also provides a pharmaceutical composition containing an pharmaceutically acceptable diluent or carrier with an antimicrobial effective amount of the general formula (I) compound or a pharmaceutically acceptable acid addition salt thereof.

The compounds of the present invention may be administered orally or parenterally to humans to treat bacterial diseases, with dosages of from about 0.1 to about 500 mg / kg / day, advantageously from about 0.5 to about 50 mg / kg / day in a single dose. Or divided into three or less divided doses can be administered orally. For intramuscular or intravenous administration, the dosage is about 0.1 to about 200 mg / kg / day, advantageously about 0.5 to about 50 mg / kg / day. Intramuscular administration is preferably administered in a single dose or in divided doses of up to 3 times, but intravenous administration may comprise continuous red wine. As will be appreciated by those skilled in the art, there will necessarily be variations depending on the weight and condition of the patient to be treated and the route of administration chosen.

The antimicrobial activity of the compounds of the present invention is determined by testing according to the in vitro bacterial standard test method described in E. Steers et al., Antibiotics and Chemotherapy, 9, 307 (1959). Can be.

The following non-limiting examples illustrate the invention. All of the melting points mentioned in the examples are not corrected. Instant chromatography is described in W. C. Still et al., Journal of Organic Chemi'stry, 43, 2923 (1978)], using silica gel (Woelm: trade name) of 32-63 μm.

Example 1

6- (S) -hydroxy-2- (1- (S) -phenethyl)-(1S, 4R) -2-azabicyclo [2.2.2] octan-3-one and 6- (R) -hydroxy Roxy-2- (1- (S) -phenethyl)-(1R, 4S) -2-azabicyclo [2.2.2] octan-3-one

Methyl-3-epoxycyclohexyl-1-carboxylate (SW Huffman et al., J. Org. Chem., 32, 700 (1967)) (39.56 g, 0.0254 moles) was dissolved in ethanol (200 ml) to obtain 500 ml. It was put in a round bottom flask. (S) -1-phenethylamine (39.17 ml, 0.304 mol) was added to the stirred solution, and the reaction mixture was refluxed for 24 hours. The ethanol was then removed in vacuo. The resulting concentrate was heated to 180 ° C. for 6 hours and then cooled, then dissolved in methanol (60 ml) and 10% aqueous NaOH (60 ml) and the mixture was refluxed for 1 hour. Thereafter, 10% aqueous hydrochloric acid (60 ml) was added to neutralize sodium hydroxide, and then methanol was removed in vacuo. The organics were redissolved in methylene chloride, washed with hydrochloric acid (50 ml) and brine (100 ml), dried (MgSO ₄ ), concentrated and then chromatographed [eluant: 75% ethyl ether / hexane (25 L), Ethyl ether (60 L), and less polar diastereomers, after all eluting out of the column, was purified by EtOAc (ethyl acetate)].

The yield of the less polar diastereomer (first title compound, compound of formula (2)) was 8.25 g (13%).

The yield of a more polar diastereomer (second title compound, compound of formula (3)) was 11.05 g (18%).

Example 2

6- (S) -hydroxy- (1- (S) -phenethyl)-(1S, 4R) -2-azabicyclo [2.2.2] octane

Lithium aluminum hydride (2.48 g, 0.0654 mol) was dissolved in freshly distilled THF (tetrahydrofuran) (50 ml), and the first title compound of Example 1 (8 g, 0.0327 mol) was added dropwise to THF solution (80 ml). . At the end of the addition, the reaction was refluxed for 16 hours. Then, TLC (thin layer chromatography) analysis using EtoAc as eluent confirmed that the reaction was completed. Water (2.48 ml) was then added deeply, followed by 15% aqueous NaOH (2.48 ml) and finally water (7.5 ml). The salt was filtered off and the organics were concentrated to afford the title compound as a white solid.

Example 3

6- (R) -hydroxy-2- (1- (S) -phenethyl)-(1R, 4S) -2-azabicyclo [2.2.2] octane

Lithium aluminum hydride (3.41 g, 0.0898 mol) was dissolved in THF (50 ml) and the second title compound of Example 1 (11 g, 0.0449 mol) was added dropwise to THF solution (100 ml). At the end of the addition the reaction was refluxed for 16 h. After 16 hours, TLC (eluent: EtOAc) analysis confirmed that the reaction was complete. Water (3.4 ml), 15% aqueous NaOH (3.4 ml) and water (10.4 ml) were added sequentially. The salt was then filtered and the organics concentrated to an oil which solidified to yield 9.70 g (94%) of the title compound as a white solid.

Example 4

2-carboethoxy-6- (S) -hydroxy- (1S, 4R) -2-azabicyclo- [2.2.2] octane

Pb (OH) ₂ (3.25) g was placed in a 500 ml Parr bottle and ethanol (30 ml) was added. The title compound of Example 2 (6.50 g, 0.028 mol) was dissolved in hot ethanol, cooled and then added to a Parr bottle containing Pb (OH) ₂ . The mixture was shaken for 20 h under H ₂ (50 ps i), whereupon TLC analysis indicated the reaction was complete. The Pb (OH) 2 was then removed by filtration and 12N aqueous HCl (2.33 ml) was added to ethanol. Ethanol was then removed in vacuo to yield 4.60 g (100%) of deprotected HCl salt. This deprotected hydrochloride (4.60 g, 0.028 mol) was dissolved in 1N aqueous NaOH (120 ml) and then cooled to 0 ° C. Ethyl chloroformate (4.03 ml, 0.042 mol) was then added dropwise to the stirred solution. The reaction was stirred for 3 hours and then the organics were extracted with EtOAc (4 × 50 ml). The organic layer was washed with 1N HCl (50 ml), dried (Na ₂ SO ₄ ) and concentrated to give 5.05 g (90%) of the title compound as a pale yellow oil. ¹ H-NMR data was the same as the result of the racemic compound of Example 18.

Example 5

2-carboethoxy-6- (R) -hydroxy- (1R, 4S) -2-azabicyclo [2.2.2] octane

Pd (OH) ₂ (5.0 g) was placed in a Parr bottle and ethanol (30 ml) was added. The title compound of Example 3 (9.50 g, 0.041 mol) was dissolved in hot ethanol (170 ml), cooled and then added to the Parr. The mixture was shaken under H ₂ (50 psi) for 20 hours at which time TLC (EtOAc) analysis showed the reaction to be complete and the catalyst was then removed by filtration. 12N aqueous HCl (3.42 ml) was added to the filtrate, and then ethanol was removed in vacuo to yield 6.77 g (100%) of deprotected HCl salt. Deprotected hydrochloride (6.72 g, 0.041 mol) was dissolved in 1N aqueous NaOH (180 ml) and then cooled to 0 ° C. Ethyl chloroformate (5.90 ml, 0.062 mol) was added dropwise to the stirred solution. The reaction was stirred for 3 hours and then the organics were extracted with EtOAc (4 × 50 ml). The combined organic layers were washed with 1N HCl (50 ml), dried (Na ₂ SO ₄ ) and concentrated to yield 7.22 g (88%) of the title compound as a light pink oil. ¹ H-NMR data was the same as the data of the racemic compound of Example 18.

Example 6

2-carboethoxy- (1S, 4R) -2-azabicyclo [2.2.2] octan-6-one

The title compound of Example 4 (4.95 g, 0.0249 mol) was dissolved in CH ₂ Cl ₂ (125 ml) and pyridinium chlorochromate (7.15, 0.0332 mol) was added slowly. The reaction mixture was stirred for 17 hours at which time TLC (EtOAc) analysis showed that some starting material was still present. Thus more pyridinium chlorochromate (1.2 g, 5.57 moles) was added. After 5 hours, TLC analysis showed that the reaction was complete. A concentrated NaHSO ₃ solution (50 ml) was added and the mixture was filtered through diatomaceous earth (celite (clave)) to separate the organic and aqueous layers. The organic layer was washed with H ₂ O (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated to pale green oil, which later solidified. The solid (about 4.65 g) was purified by flash chromatography (eluent: EtOAc) to give a pale green powder, which was triturated with EtOAC / hexanes to give 1.75 g (35.7%) of the title compound as a pale green solid [melting point]. 82-85 ° C. [α] _D 59.4 ° (CHCl ₃ )]. ¹ H-NMR data was the same as the data of the racemic compound of Example 19.

Example 7

2-carboethoxy- (1R, 4S) -2-azabicyclo [2.2.2] octan-6-one

The title compound of Example 5 (7.12 g, 0.0358 mol) was dissolved in CH ₂ Cl ₂ (175 ml) and pyridinium chlorochromate (10.28 g, 0.0477 mol) was added slowly. The reaction mixture was stirred for 16 hours at which time TLC (EtOAc) analysis showed that the starting material was still present. Stock pyridinium chloromate (2.3 g, 0.011 mol) was added and the reaction mixture was stirred for another 5 hours. Concentrated NaHSO ₃ solution (75 ml) was added and the reaction mixture was filtered over diatomaceous earth [Celite ™] to separate the layers. The organic layer was washed with molar (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated to a pale green oil, which solidified to a green solid. This solid (about 5.8 g) was purified by flash chromatography (eluent: EtOAc) to give 5.5 g of a white solid which was triturated with EtOAc / hexanes to give 3.95 g (56%) of the title compound [melting point 82-]. 85 ° C., [α] _D −56.4 ° (CHCl ₃ )].

¹ H-NMR data was the same as the data of the racemic compound of Example 19.

Example 8

6- (S) -benzylamino-2-carboethoxy- (1S, 4R) -2-azabicyclo [2.2.2] octane and 6- (R) -benzylamino-2-carboethoxy- (1S, 4R) -2-azabicyclo [2.2.2] octane

The title compound of Example 6 (2 g, 0.010 mol) was dissolved in benzene (60 ml). Benzylamine (1.22 ml, 0.011 mole) was added and the mixture was heated to reflux for 24 hours to remove H ₂ O with a Dean-Stark trap. After 24 hours, benzene was removed in vacuo, the residue was cooled to 0 ° C., diluted with ethanol (80 ml) and then treated with NaBH ₄ (1.92 g, 0.051 mol) in small portions. After 3 hours, 1N aqueous HCl (55 ml) was added very slowly to the flask. Ethanol was removed in vacuo and replaced with EtOAc. The layers were separated and the aqueous layer was brought to pH 14 and extracted with EtOAc (2 × 50 ml). The EtOAc layer was dried (Na ₂ SO ₄ ) and concentrated to a clear oil, and the resulting oil (2.4 g) was purified by flash chromatography (eluant: EtOAc). The less polar material (first title compound) was 0.83 g (28%), [α] _D 22.9 ° (CHCl ₃ ). NMR data were the same as the racemic compound 20A data of Example 20. The more polar substance (second title compound) was 0.43 g (14.7%) and [α] _D 6.2 ° (CDCl ₃ ). The 1 H-NMR data was the same as the data of the racemic compound 20B of Example 20.

Example 9

6- (S) -benzylamino-2-carboethoxy- (1R, 4S) -2-azabicyclo [2.2.2] octane, and 6- (S) -benzylamino-2-carboethoxy- (1R , 4S) -2-azabicyclo [2.2.2] octane

The title compound of Example 7 (2.1 g, 0.0107 mol) was dissolved in benzene (60 ml) and benzylamine (1.28 ml, 0.012 mol) was added. This mixture was heated to reflux for 24 hours using a Dean-Stark trap to remove H ₂ O. After 24 hours, the bezel was removed in vacuo. The residue was cooled to 0 ° C. and diluted with ethanol (50 ml) to treat NaBH ₄ (2.03 g, 0.053 mol) in small portions. After 3 hours, 1N aqueous HCl (55 ml) was added very slowly to the flask. Ethanol is removed in vacuo and EtOAc is replaced. The layers were separated to make the aqueous layer pHl4 and the organics extracted with EtOAc (2 x 50 ml). EtOAc layers were combined, dried (Na ₂ SO ₄ ), concentrated to the same oil (ca. 2.2 g) and purified by flash chromatography (eluant: EtOAc). Yield of the less polar material (first title compound) was 1 g (32%) and [α] _D -22.4 ° (CHCl ₃ ). NMR data were the same as those of the racemic compound 20A of Example 20. The more polar material (second title compound) was 0.50 g (16%) and [α] _D -5.3 ° (CHCl ₃ ). NMR data were the same as the racemic compound 20B of Example 20.

Example 10

6- (R) -benzelamino- (1S, 4R) -1-azabicyclo [2.2.2] octane dihydrobromide

The second title compound (0.40 g 1.39 mmol) of Example 8 was dissolved in 48% aqueous HBr (8 ml) and heated to reflux for 2.5 hours. The solvent was then removed through a water aspirator and the remaining water was removed by an azeotropic mixture formed with isopropyl alcohol. The residue was then triturated in ethyl ether to afford the title compound. Yield: 0.525 g (100%); [α] _D 31.2 ° (H ₂ O): Melting point 271-274 ° C

NMR data were the same as the data of the racemic compound of Example 23.

Example 11

6- (S) -benzylamino- (1R, 4S) -2-azabicyclo [2.2.2] octane dihydrobromide

The second title compound (0.41 g, 1.39 mmol) of Example 9 was dissolved in 48% aqueous HBr and heated to reflux for 2.5 hours. Solvent was removed via aspirator and residual water was removed by an azeotrope formed with isopropyl alcohol. The residue was then triturated with ethyl ether to afford 0.50 g (93%) of the title compound as a tan solid.

[α] _D -35.6 °: (H ₂ O): Melting point 270-274 ° C

NMR data were the same as the data of the racemic compound of Example 23.

Example 12

6- (S) -benzylamino- (1S, 4R) -2-azabicyclo [2.2.2] octane dihydrobromide.

The first title compound (0.72 g, 2.50 mmol) of Example 8 was dissolved in 48% aqueous HBr (10 ml) and then heated to reflux for 2 hours. The solvent was removed under a fixed stream of N ₂ and the remaining water was removed by isopropyl alcohol azeotrope. The salt was then triturated in ethyl ether to yield 0.940 g (94%) of the title compound. Melting point 241-245 ° C .; α _D 27.0 ° (H ₂ O).

NMR data were the same as the data of the racemic compound of Example 21.

Example 13

6- (R) -benzylamino- (1S, 4S) -2-azabicyclo [2.2.2] octane dihydrobromide.

The first title compound (0.78 g, 2.71 mmol) of Example 9 was dissolved in 48% aqueous HBr (10 ml) and heated to reflux for 2 hours. The solvent was then evaporated under a fixed stream of N ₂ and the remaining water was removed by an azeotrope formed with isopropyl alcohol. The resulting salt was triturated in ethyl ether to give 1 g (98%) of the title compound. Melting point 241-245 ° C .; α _D 31.5 ° (CHCl ₃ ).

NMR data were the same as the data of the racemic compound of Example 21.

Example 14

7- (6- (R) -amino- (1S, 4R) -2-azabicyclo [2.2.2] oct-2-yl) -1-cyclopropyl-1, 4-dihydro-6-fluor-4 Oxo-3-quinolinecarboxylic acid.

1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5189 g, 1.96 mmol) and the compound of Example 10 (0.543 g, 1.44 mmol) were pyridine ( 10 ml). DBU (0.542 ml, 2.5 equiv) was then added and the mixture was heated to 70 ° C. for 17 h. The pyridine was then removed in vacuo and the resulting brown solid was purified by flash chromatography (90 g of silica gel; eluent: 5% methanol / CHCl ₃ ) to give 0.58 g of a yellow solid. This solid was dissolved in methanol (70 ml) and added to a Parr bottle containing Pb (OH) ₂ (0.70 g) and ethanol (5 ml). The mixture was shaken for 3 h under H ₂ (45 p. S. I), filtered through diatomaceous earth (Celite ™) and concentrated. The filtrate was crystallized from methanol / CHCl ₃ and purified by chromatographic chromatography (silica gel 5 g; eluent: 2% to 5% methanol / CHCl ₃ ) using a minimum amount of silica gel, ground with methanol / CHCl ₃ and then white. 45 mg of the title compound was obtained as a solid. [α] _D 23.7 ° (DMSO), Melting point 310 ° C.

NMR data were the same as the data of the racemic compound of Example 24.

Example 15

7- (6- (S) -amino- (1R, 4S) -2-azabicyclo [2.2.2] oct-2-yl) -1-cyclopropyl-1, 4-dihydro-6-fluor-4 Oxo-3-quinolinecarboxylic acid.

In a similar manner to Example 14, the title compound (0.41 g) of Example 11 was added to 1-cyclopropyl-6, 7-difluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid in the presence of DBU. Coupling and catalytic hydrogenation of the product removed the benzyl group to yield 30 mg of the title compound as a light yellow solid. [Melting point 310 ° C., [α] _D -43.4 ° (DMSO).

NMR data were the same as in the racemic compound of Example 24.

Example 16

7- (6- (S) -amino- (1S, 4R) -2-azabicyclo [2.2.2] oct-2-yl) -1-cyclopropyl-1, 4-dihydro-6-fluor-4 Oxo-3-quinolinecarboxylic acid.

In a similar manner to Example 14, the title compound (0.80 g) of Example 12 was dissolved in 1-cyclopropyl-6, 7-difluorozo-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid. And the product were catalytically hydrogenated similarly to the above to remove benzyl groups to yield 0.24 g of the title compound. [Melting Point 267 to 270 ° C, [α] _D 66.3 ° (DMSO).

NMR data were the same as in the racemic compound of Example 22.

Example 17

7- (6- (R) -amino- (1R, 4S) -2-azabicyclo [2.2.2] oct-2-yl) -1-cyclopropyl-1, 4-dihydro-6-fluor-4 Oxo-3-quinolinecarboxylic acid.

In a similar manner to Example 14, the title compound (0.80 g) of Example 13 was added to 1-cyclopropyl-6, 7-difluor-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid in the presence of DBU. Coupling and the product catalytic hydrogenation to remove benzyl groups yielding 0.16 g of the title compound as a solid. [Melting point 268 to 271 ° C., [α] _D -69.3 ° (DMSO)]

NMR data were the same as in the racemic compound of Example 22.

Example 18

Endo-2-carboethoxy-6-hydroxy-2-azabicyclo [2.2.2] octane

2-benzyl-6-endo-hydroxy-2-azabicyclo [2.2.2] octane (RF Borne et al., J. Het. Chem., 10, 241 (1973)) 22.02 g (101.3 mmol), 12 M A mixture of 16.88 ml (202.6 mmol) hydrochloric acid, 5.00 g Pb (OH) ₂ and 370 ml anhydrous ethanol was hydrogenated at 40 psi for 16 hours on a Parr Shaker apparatus. Then additional 5.00 g of Pd (OH) ₂ were added and hydrogenation continued for 24 hours. The mixture was filtered through diatomaceous earth (Celite®) and removed by rotary evaporation with ethanol. The solid residue (24 g) was diluted with 200 ml of 2N aqueous sodium hydroxide solution and treated dropwise with 16.49 g (152 mmol) of ethyl chloroformate at 0 ° C. After stirring for 1 h, the mixture was extracted with EtOAc (4 × 100 ml) and the dried (MgSO ₄ ) extract was evaporated to give 20.06 g (99%) of the title compound (Rf 0.3, EtOAc) as an oil:

Example 19

2-carboethoxy-2-azabicyclo [2.2.2] octane-6-one

To a solution of 20.00 g (100 mmol) of the title compound of Example 18 in 700 ml of dichloromethane was added 32.46 g (150 mmol) of pyridinium chlorochromate in small portions. The mixture is stirred for 5.5 hours, at which time the mixture is washed with 10% aqueous NaHSO ₃ solution (4 × 200 ml) and water (2 × 200 ml), dried (MgSO ₄ ) and evaporated to give 22.5 g of oil. did. The oil was purified by flash chromatography (eluant: 1% methanol / CHCl 3) to give an oil which was crystallized from pentane to give 2-carboethoxy-2-azabicyclo [2.2.2] octane-6-silver ( 14.23 g of Rf 0.75, 10% methanol / CHCl ₃ ) were obtained. [Melt Point 68.5-69.5 ° C.]:

Mass spectrum m / e 197 (M &lt; + &gt;), 169.140 (base).

Example 20

Endo and exo-6-benzylamino-2-carboethoxy-2-azabicyclo [2.2.2] octane.

To a mixture of 350 mg (1.8 mmol) of the title compound of Example 19, 246 mg (2.3 mmol) of benzyl amine, 108 mg (1.8 mmol) of acetic acid and 8 ml of methanol was added 453 mg (7.2 mmol) of sodium cyanoborohydride. At room temperature, the mixture was adjusted to pH 6 by periodically adding acetic acid while stirring. After stirring for 16 hours, the solvent was removed and 25 ml of 1N HCl aqueous solution was carefully added to the solid residue until gas (hydrogen cyanide) release ceased. The acidic mixture was washed with EtOAc (2 × 50 ml), basified to pH 12 and extracted with EtOAc (2 × 50 ml). The extracts were combined and dried (K ₂ CO ₃ ) and evaporated to give 459 mg of oil. The oil was separated by flash chromatography (eluant: 2.5% methanol / CHCl ₃ ) to give endo-6-benzylamino-2-carboethoxy-2-azabicyclo [2.2.2] octane (Compound 20A) ( 197 mg (38%) of Rf 0.55, 10% methanol / CHCl ₃ ) were obtained.

From the later fractions 84 mg (16%) of exo-6-benzylamino-2-carboethoxy-azabicyclo [2.2.2] octane (Compound 20B) (Rf 0.43, 10% MeOH / CHCl ₃ ) were obtained. .

Example 21

Endo-6-benzylamino-2-izabicyclo [2.2.2] octin dihydrobromide.

A mixture of 186 mg (0.64 mmol) of compound 20A and 2 ml of 48% HBr aqueous solution was heated to reflux for 2 hours. The solvent was removed by distillation (aspirator vacuum) and the residue was azeotropic distilled with isopropanol to leave white powder which was triturated with ether to give 244 mg (92%) of the title compound.

Example 22

Endo-7- (6-amino-2-azabicyclo [2.2.2] oct-2-yl) -1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid

2.36 g (6.2 mmol) of the title compound of Example 21, 1.97 g (6.9 mmol) of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.30 g of DBU (15.5 mmol) and 20 ml of pyridine were heated under N _{2 at} 70 ° C. for 16 h. The solvent was removed and the oily residue was purified by flash chromatography (eluant: 4% methanol-CHCl ₃ ) to endo 7- (6-benzylamino-2-azabicyclo- [2.2.2] oct-2-yl) -1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid (Rf 0.39, 18: 2: 1 CHCl ₃ : MeOH: acetic acid) and unreacted 1-cyclopropyl 3.16 g of a mixture of -6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid were obtained. This mixture was then hydrogenated for 2.5 hours in 350 ml of methanol at 50 p.si in the presence of 3.5 g of Pb (OH) on a Parr shaker apparatus. The mixture was filtered and the residue was triturated to give 2.01 g of a yellow solid, which was purified by flash chromatography (eluant: 10% methanol-CHCl ₃ ) to give 0.98 g of a yellow solid. The yellow solid was triturated in hot EtOAc / isopropanol to give 0.530 g (18%) of the title compound as a pale yellow powder. (Melting point 255-257 ° C.).

High split mass spectrum, analysis for C ₂₀ H ₂₂ FN ₃ O ₃ :

Calculated Value: m / e 371.1646,

Found: m / e 371.1662.

Example 23

Exo-6-benzylamino-2-azabicyclo [2.2.2] octane dihydrobromide

A mixture of 76 mg (0.26 mmol) of compound 20B and 2 ml of an aqueous 48% HBr solution was heated to reflux for 2 hours. The solvent was removed by kind (aspirator vacuum) and the residue was azeotropic distilled with isopropanol to leave a white solid which was triturated with ether to give 98 mg (99%) of the title compound.

Example 24

Exo-7- (6-amino-2-azabicyclo [2.2.2] oct-2-yl) -1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid

160 mg (0.42 mmol) of the title compound of Example 23, 133 mg (0.50 mmol) of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.257 g of DBU ( 1.68 mmol) and pyridine 4 ml mixture was heated to 40 ° C. under N _{2 for} 56 h. Remove the solvent and purify the oily residue by instant chromatography using 2.5-5% methanol / CHCl ₃ eluent to exo-7- (6-benzylamino-2-azabicyclo [2.2.2] oct-2 -Yl) -1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid (Rf 0.2, CHCl ₃ : methanol: acetic acid 18: 2: 1) 128 mg as a yellow solid Obtained and then hydrogenated in 50 ml of methanol at 40 p.si in the presence of 100 mg of Pb (OH) ₂ . The catalyst was filtered off and the filtrate was evaporated to yield 86 mg of a yellow solid. This was triturated with isopropanol to give 36 mg (23%) of the title compound (Rf 0.05, CHCl ₃ : methanol: acetic acid 18: 2: 1) as a tan solid (melting point 234-240 ° C.):

High split mass spectrum, for C ₂₀ H ₂₂ FN ₃ O ₃ :

Calculated m / e 371.1655,

Found m / s 371.1670.

Example 25

Endo-7- (6-amino-2-azabicyclo [2.2.2] oct-2-yl) -1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-4-oxo-3 Quinolinecarboxylic acid.

290 mg (0.76 mmol) of Compound 20A, 1-cyclopropyl-6, 8-difluoro-1, 215 mg (0.76 mmol) of 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 289 mg (1.89 mmol) of DBU, and A mixture of 5 ml of pyridine was heated to 70 ° C. for 16 h under N ₂ . The solvent was removed and the residue was purified by chromatography over an instant using 10% methanol / CHCl ₃ eluent to give 7- (6-benzylamino-2-azabicyclo [2.2.2] oct-2-yl) -1- Cyclopropyl-6, 8-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid and unreacted 1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-4 283 mg of a mixture of oxo-3-quinolinecarboxylic acid was obtained. The mixture was then hydrogenated for 1.5 h at 50 p.si in 50 ml of methanol in the presence of 100 mg of Pd (OH) ₂ . Filtration removes the catalyst and the solvent is evaporated to give an oil which is purified by chromatography over an instant using 10% methanol / CHCl ₃ eluent to give the title compound (Rf 0.08, CHCl ₃ : methanol: acetic acid as light yellow solid). 18: 2: 1) 27 mg (10%) was obtained (melting point 251-253 degreeC).

For high split mass spectra, C ₂₀ H ₂₁ F ₂ N ₃ O ₃ :

Calculated m / e 389.1579,

Found m / s 389.1565.

Example 26

Endo-2-benzyloxycarbonyl-6-hydroxy-2-azabicyclo [2.2.2] octane

50 p.si of a mixture of 5.6 g (25.8 mmol) of endo-2-benzyl-6-hydroxy-2-azabicyclo [2.2.2] octane, 120 ml of anhydrous ethanol, 10 ml of concentrated aqueous hydrochloric acid solution and 2.8 g of 10% pd / C Hydrogenated for 48 hours. During the hydrogenation, ie at 16 and 20 hours additional amounts of catalyst (1.0 g each) and concentrated aqueous hydrochloric acid solution (10 equivalents and 6 equivalents, respectively) were added. The catalyst was filtered off, the filtrate was evaporated and the residue was crystallized from isopropanol to give a white solid which was dissolved in 60 ml of water. The mixture was then basified to pH 10 with solid K ₂ CO ₃ , cooled to 0 ° C. and treated with 5.88 g (34.4 mmol) benzylchloroformate. After stirring for 16 hours while slowly warming to room temperature, the mixture was extracted with EtOAc (3 × 100 ml). The combined extracts were dried (K ₂ CO ₃ ) and evaporated to yield 7 g of oil, which was purified by chromatography over an instant using EtOAc: hexane (1: 1) eluent to give the title compound (Rf 0.27, EtOAc). : Hexane 1: 1) 6.09 (90%) was obtained.

Example 27

2-benzyloxycarbonyl-2-azabicyclo [2.2.2] octane-6-one

A solution of 6.00 g (2.30 mmol) of endo-2-benzyloxycarbonyl-6-hydroxy-2-azabicyclo [2.2.2] octane in 45 ml of acetone was cooled to 0 ° C. and the Jones reagent (K. Bowden et al., J. Chem. Soc., 39 (1946)) was treated dropwise with 10.0 ml (26.7 mmol). After stirring for 2 hours, the solvent was removed by evaporation and the residue was diluted with 50 ml of water and extracted with EtOAc (2 × 50 ml). The combined EtOAc extracts were washed with water (2 × 50 ml), and saturated aqueous NaHCO ₃ (2 × 30 ml), dried (K ₂ CO ₃ ) and evaporated to 2-benzyloxycarbonyl-2-azabicyclo [2.2 as oil. 4.2 g (70%) of octane-6-one (Rf 0.46, EtOAc in hexane (1: 1)) was obtained.

Example 28

Endo and exo-6-benzylamino-2-benzyloxycarbonyl-2-azabicyclo [2.2.2] octane

To a mixture of 4.05 g (15.6 mmol) of the title compound of Example 27, 1.70 (15.9 mmol) benzylamine, and 0.94 g (15.6 mmol) of acetic acid in 50 ml of methanol, 3.92 g (62.4 mmol) of sodium cyanoborohydride were added. The mixture was stirred for 16 hours, with the addition of a minimum amount of acetic acid to maintain the pH at 6. The solvent was removed by evaporation and the semi-solid residue was carefully treated with 200 ml of 2N HCl aqueous solution (HCN release). After stirring for 45 more minutes, the mixture was washed with ether (3 x 100 ml), basified to pH 14 with 4N aqueous NaOH solution and extracted several times with EtOAc. The combined EtOAc extracts were dried (K ₂ CO ₃ ) and evaporated to give 2.2 g of oil. Chromatography was used to separate the title compound to give less than 675 mg (12%) of the less polar endo diastereomer as oil (Rf 0.32, EtOAc), and more exo diastereomer than the title compound. 310 mg (6%) of isomer was obtained as an oil (Rf 0.18, EtOAc). ¹ H-NMR (300 MHz, CDCl ₃ ) of the diastereomeric mixture showed two singlets (2H, respectively) at δ 3.85 and 5.16.

Example 29

Endo-6-benzylethylamino-2-benzyloxycarbonyl-2-azabicyclo [2.2.2] octane

Endo-6-benzylamino-2-benzyloxycarbonyl-2-azabicyclo [2.2.2] 500 mg (1.4 mmol) octane, 5 ml DMF, 5 ml benzene, 592 mg (4.2 mmol) K ₂ CO ₃ and ethyl iodide A mixture of 240 mg (1.54 mmol) was stirred at 60 ° C. for 4 days. Additional ethyl iodide (1 equiv) was added on day 3 while the reaction was detected by TLC. The solvent was removed by evaporation and the residue was extracted with EtOAc, filtered and evaporated to give an oil. It was purified by chromatography using an EtOAc eluent to afford 390 mg (72%) of the title compound as an oil.

Example 30

Endo-6-benzylethylamino-2-azabicyclo [2.2.2] octane dihydrobromide

A mixture of 250 mg (0.66 mmol) of endo-6-benzylethylamino-2-benzyloxycarbonyl-2-azabicyclo [2.2.2] octane and 2.5 ml of 48% aqueous HBr solution was allowed to stand for 16 hours at room temperature. The solvent was removed by evaporation and the residue was co-evaporated several times with isopropanol and triturated in ether to give 128 mg (47%) of the title compound.

Example 31

Endo-1-cyclopropyl-1, 4-dihydro-7- (6-ethylamino-2-azabicyclo [2,2,2] oct-2-yl) -6-fluoro-4-oxo-3 Quinolinecarboxylic acid

Ender-6-benzylethylamino-2-azabicyclo [2.2.2] octane dihydrobromide 100 mg (0.25 mmol), 1-cyclopropyl-6, 7-difluoro-1,4-dihydro-4-oxo A mixture of 67 mg (0.26 mmol) of 3--3-quinoline carboxylic acid, 152 mg (1.00 mmol) of DBU and 4 ml of pyridine was heated to 70 ° C. for 16 hours. The solvent was removed by evaporation and the residue crystallized from methanol. The solids were filtered off and the mother liquor was purified by chromatography over an instant using 10% methanol / CHCl ₃ eluent to endo-7- (6-benzylethylamino-2-azabicyclo [2.2.2] oct-2-yl). -1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinoline carboxylic acid (Rf 0.25, CHCl ₃ : methanol: acetic acid 18: 2: 1) 38 mg (32%) total Combined with solids). The product was dissolved in 20 ml of methanol and hydrogenated for 3.5 hours in the presence of 40 mg of Pb (OH) ₂ at 50 p.si on a Parr shaker apparatus. The catalyst was filtered off, the solvent was evaporated, and the residue was purified by chromatography over an instant using 10% methanol / CHCl ₃ eluent to give 6 mg of the title compound (Rf 0.05, CHCl ₃ : methanol: acetic acid 18: 2: 1). 16%) was obtained as a solid (melting point 230 ° C. (decomposition)):

High Split Mass Spectrum, for C ₂₂ H ₂₆ FN ₃ O ₃ :

Calculated m / e399.1958,

Found m / s 399.1978.

Example 32

Exo-6-benzylethylamino-2-benzyloxycarbonyl-2-azabicyclo [2.2.2] octane

Exo-6-benzylamino-2-benzyloxycarbonyl-2-azabicyclo [2.2.2] octane 250 mg (0.7 mmol), K ₂ CO ₃ 296 mg (2.1 mmol), 5 ml benzene, 5 ml DMF and ethyl iodide 120 mg (0.77 mmol) of the mixture was heated to 60 ° C. for 7 days. Additional ethyl iodide (4 equiv) was added on day 4 while the reaction was detected by TLC. The solvent was removed by evaporation and the residue was extracted with EtOAc, filtered and evaporated to give an oil. It was purified by chromatography using EtOAc: hexane (1: 1) eluent to afford 200 mg (74%) of the title compound as an oil (Rf 0.57, EtOAc):

Example 33

Exo-6-benzylethylamino-2-azabicyclo [2.2.2] octane dihydrobromide

A mixture of 200 mg (0.5 mmol) of exo-6-benzylethylamino-2-benzyloxycarbonyl-2-azabicyclo [2.2.2] octane and 2 ml of 48% HBr aqueous solution was stirred at room temperature for 16 hours. The solvent was removed by evaporation and the residue co-evaporated several times with isopropanol to give a solid. This was triturated in ether to give 142 mg (66%) of the title compound.

Example 34

Exo-1-cyclopropyl-1,4-dihydro-7- (6-ethylamino-2-azabicyclo [2,2,2] oct-2-yl) -6-fluoro-4-oxo-3 Quinolinecarboxylic acid

Exo-6-benzylethylamino-2-azabicyclo [2.2.2] octane dihydrobromide 120 mg (0.30 mmol), 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo A mixture of 95 mg (0.36 mmol) of -3-quinoline carboxylic acid, 182 mg (1.20 mmol) of DBU and 4 ml of pyridine was stirred at 70 ° C. for 16 hours. The solvent was removed by evaporation and the residue was purified by chromatography using flash chromatography using 3% acetic acid in CHCl ₃ , 7% methanolic eluent and exo-7- (benzyl ethylamino-2-azabicyclo [2.2. 2] Oct-2-yl) -1-cyclopropyl-1, 134 mg of acetic acid salt of 4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid were obtained. The salt was treated with saturated aqueous NaHCO ₃ solution, extracted with CHCl ₃ , dried (K ₂ CO ₃ ) and evaporated to give the free base. The free base was then hydrogenated for 4 hours in 20 ml of methanol at 50 p.si in the presence of 50 mg of Pd (OH) ₂ on a Parr shaker apparatus. The catalyst was removed by filtration and the filtrate was concentrated to give an oil. This was purified by chromatography using 20% methanol / CHCl ₃ eluent, to give 31 mg (45%) of the title compound (Rf 0.05, CHCl 3: MeOH: AcOH 18: 2: 1) as a solid (melting point: 159 to 161 ° C.). Obtained.

High Split Mass Spectrum, for C ₂₂ H ₂₆ FN ₃ O ₃ :

Calculated Value: m / e 399.1958,

Actual value: m / s 399.1986.

Example 35

The antimicrobial activity of the compounds of Examples 14-17, 22, 24, 25, 31 and 34 was tested. They are Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, E. Coli in amounts less than 15 μg / ml. It has been shown to be active against Klebsiella, Pasteurella, Serratia, and Neisseria gonorrhea.

Claims (6)

A compound of formula (I) or a pharmaceutically acceptable salt thereof.

Wherein R ¹ is hydrogen, C ₁ -C ₆ alkyl or a pharmaceutically acceptable cation, Y is cyclopropyl, ethyl or p-fluorophenyl, X is hydrogen or fluorine, or X and Y together

or

Form a group, R ² is

Wherein R ² is hydrogen or C ₁ -C ₄ alkyl. The compound of claim 1, wherein R ₂ is

or

Phosphorus compounds. The compound of claim 1 or 2, wherein R ³ is hydrogen. The compound of claim 1 or 2, wherein Y is cyclopropyl. The compound of claim 1 or 2 wherein X is hydrogen. An antimicrobial pharmaceutical composition comprising an antimicrobial effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.